The research in this grant is designed to dissect out the autonomic mechanisms of neurally-mediated syncope, to classify patients, and to unravel how treatments work. Little is known about the autonomic response to head-up tilt in patients with neurally-mediated syncope. The first primary aim of this grant is to evaluate in patients with neurally- mediated syncope, resting autonomic function and the reflex response of the autonomic nervous system to head-up tilt using RR variability and baroreflex sensitivity. This research will test the hypothesis that patients with neurally-mediated syncope will have an exaggerated autonomic response to head-up tilt (with greater vagal withdrawal and sympathetic excitation) that is related to excessive venous pooling. We plan to develop and test a new technique which uses strain-gauge technology to determine changes in calf volume during head-up tilt. Measurements of venous pooling will be related to autonomic responsiveness providing an integrated analysis of the autonomic pathophysiology of neurally-mediated syncope. This will permit clarification of the relative importance of an initiating stimulus (excessive venous pooling) versus an inappropriate autonomic response to head-up tilt (exaggerated vagal withdrawal) in the pathogenesis of this disorder. The second primary aim of this grant is to evaluate the autonomic effects of two types of treatments for patients with neurally-mediated syncope: drugs which act on the sympathetic and parasympathetic nervous systems The autonomic effects of these drugs will be made using RR variability, baroreflex sensitivity, and the heart rate response to atropine. The effects of these drugs on the autonomic response to head-up tilt will be evaluated and related to the interaction of these drugs with venous pooling. We expect that integration of a better understanding of the autonomic mechanisms operative in the genesis and treatment of neurally- mediated syncope, will provide a more logical and effective approach to treatment. The evaluation of therapy will be made in randomized placebo- controlled trials of these drugs which will permit an initial assessment of the relative efficacy of these drugs (compared with placebo) in their ability to prevent tilt table induced syncope. After the randomized sequence of tilt table studies (placebo and drug), all patients will be treated with a drug and followed for one year, irrespective of the results of the tilt table study on the drug. This will allow an assessment of the ability of tilt table testing on drug therapy to predict long-term efficacy. This research will take place within the Syncope Center and a newly furnished Autonomic Function Laboratory in the Irving Center for Clinical Research. During this CIDA, I will be trained in the measurement of venous plethysmography and direct sympathetic nerve recordings. Extensive training in biostatistics, experimental design and the operation of clinical trials will take place within Dr. Bigger's Research Unit.